1) Field of the Invention
This invention relates to a process for the preparation of .alpha.-L-aspartyl-L-phenylalanine methyl ester (hereinafter abbreviated as ".alpha.-APM").
.alpha.-APM is widely known as a dipeptide sweetener. It has good sweetness characteristics and a high degree of sweetness close to 200 times the sweetness of sucrose, whereby its demand as a dietetic sweetener is increasing considerably.
2) Description of the Related Art
.alpha.-APM is a dipeptide compound formed of L-aspartic acid and L-phenylalanine methyl ester. Although a number of processes have already been known, centering around chemical preparation processes, as to its preparation, the common process is to use an N-protected-L-aspartic anhydride and L-phenylalanine methyl ester as starting materials.
For example, a process is known in which .alpha.-APM is obtained by reacting N-benzyloxycarbonyl-L-aspartic anhydride and a salt of L-phenylalanine methyl ester in an inert solvent containing a base in an amount at least equivalent to the salt of L-phenylalanine methyl ester, dissolving the thus-formed N-benzyloxycarbonyl-.alpha.-L-aspartyl-L-phenylalanine methyl ester (hereinafter as abbreviated as "Z-.alpha.-APM") as an alkali salt in water, acidifying the solution, extracting the solution with a water-immiscible organic solvent and then subjecting the extract to catalytic hydrogenation in methanol (U.S. Pat. 3,808,190). In this process, however, hydrolysis of Z-.alpha.-APM takes place due to the use of the acid and alkali upon the extraction so that .alpha.-L-aspartyl-L-phenylalanine (hereinafter abbreviated as ".alpha.-AP" is byproduced subsequent to the catalytic hydrogenation.
Further, Japanese Patent Publication No. 40071/1976 discloses a process for obtaining .alpha.-APM, in which Z-.alpha.-APM obtained by condensation of N-benzyloxycarbonylaspartic anhydride and L-phenylalanine methyl ester in an organic solvent is subjected to catalytic hydrogenation in acetic acid or a mixed solution of acetic acid and water as a solvent. This process, however, requires removal of acetic acid by distillation in order to isolate e-APM after the reduction. 3-Benzyl-6-carboxymethyl-2,5-diketopiperazine (hereinafter abbreviated as "DKP") which does not have sweetness is however formed during the distillation, leading to a reduction in yield and deterioration in quality.
Japanese Patent Publication No. 25537/1982 discloses a process for the preparation of .alpha.-APM, in which Z-.alpha.-APM is reduced using a platinum-group catalyst in the presence of an aqueous solution of a mineral acid and then neutralizing the aqueous solution of the resultant reaction product. This process, however, is accompanied by the byproduction of .alpha.-AP due to hydrolysis of the resulting .alpha.-APM by the mineral acid during the reduction and requires the step of neutralizing the aqueous solution with a base subsequent to the reduction. It is also impossible to avoid mixing of salts, which have been formed from such mineral acid and base, in .alpha.-APM so isolated, resulting in a reduction in the quality of Aspartame.
Japanese Patent Publication No. 25538/1982 discloses a process for the preparation of .alpha.-APM, in which N-benzyloxycarbonylaspartic anhydride and L-phenylalanine methyl ester are reacted in an organic aliphatic solvent, the resultant Z-.alpha.-APM is, either after isolation or without isolation, subjected to catalytic hydrogenation in the presence of at least one catalyst selected from the group consisting of iron-group catalysts and platinum-group catalysts, resulting .alpha.-APM is dissolved in an aqueous solution of a mineral acid, and the solution is then neutralized. The Z-.alpha.-APM so obtained is, however, in a solid form unsuited for reduction, and it is difficult to grind the same. This process is accompanied by the additional drawbacks that, like the above-described process due to the use of the aqueous solution of the mineral acid, .alpha.-APM is hydrolyzed to byproduce .alpha.-AP having no sweetness and inorganic salts are undesirably mixed in the .alpha.-APM so purified.
In any of the conventional art described above, use of N-benzyloxycarbonyl-L-aspartic acid as a starting material makes it impossible to avoid byproduction of .beta.-APM besides .alpha.-APM as the target product. This .beta.-APM does not have sweetening effects but conversely gives bitterness so that its inclusion lowers the commercial value of .alpha.-APM.
As a process for isolating .alpha.-APM from such a mixture of .alpha.-APM and .beta.-APM, Japanese Patent Publication No. 6305/1974 discloses a process in which .alpha.-APM and .beta.-APM are brought into contact with .beta.-resorcylic acid in an aqueous medium to convert .alpha.-APM into a sparinglysoluble addition product so that .alpha.-APM is separated from .beta.-APM as an impurity. Although this process can separate .alpha.-APM from the impurity contained in a large amount, it requires cumbersome operation due to the use of .beta.-resorcylic acid in the same amount as .alpha.-APM and .beta.-APM and the recrystallization of the .alpha.-APM addition product from water subsequent to its isolation from a dilute aqueous solution thereof and, moreover, it is economically disadvantageous because the recovery rate of the expensive .alpha.-APM is low.
On the other hand, Japanese Patent Publication No. 41425/1974 discloses a process in which .alpha.-APM containing .beta.-APM is brought into contact with a hydrohalogenic acid in an aqueous medium to form the sparingly-soluble hydrohalide of .alpha.-APM, thereby separating .beta.-APM copresent as an impurity. This separation process which is conducted using an aqueous solution of the hydrohalogenic acid in an excess amount is good in separating .beta.-APM from .alpha.-APM in which the .beta.-APM is contained. It is, however, accompanied by such drawbacks that, because of the dissolution in the aqueous solution of the hydrohalogenic acid, hydrolysis of the methyl ester of .alpha.-APM tends to proceed, the recovery rate of the hydrohalide of .alpha.-APM is low and an expensive acid-resistant material must be used as a material for a reactor.
To obtain .alpha.-APM from a mineral acid salt of .alpha.-APM once isolated as an acid addition product as described above, a neutralization step is needed. This neutralization is generally conducted by dissolving the mineral acid salt of .alpha.-APM in water, adding a base to the solution to neutralize the same and then separating .alpha.-APM formed as crystals. Since .alpha.-APM is lost in a substantial amount in the aqueous solution, the yield becomes low. The filtrate contains a large amount of salts formed from the mineral acid and the base, so that it is difficult to use it again in the preceding step. As .alpha.-APM isolated in this manner contains salts in a large amount, operations such as recrystallization and desalting are needed to obtain the final product so that the yield is lowered further.
As has been described above, the previously-known preparation processes of .alpha.-APM are accompanied by one. or more drawbacks and are not fully satisfactory as industrial preparation processes. To solve the problems in the conventional reducing steps of Z-.alpha.-APM, in particular, it is desired to conduct a reducing reaction in an aqueous medium. However, no process has heretofore been available to efficiently obtain an aqueous Z-.alpha.-APM suspension suited for reduction in such an aqueous solvent. Moreover, no process has been found for obtaining .alpha.-APM with high purity in high yield upon isolation of .alpha.-APM subsequent to catalytic reduction of Z-.alpha.-APM containing Z-.beta.-APM.